Preparation method of votioxetine

A technology of vortioxetine and propylene diamine, applied in the field of medicinal chemistry, can solve the problems of high price of resin palladium removing material, limited effect, difficult to clean and the like, and achieves the effect of good palladium removing effect and reduced operation steps.

Pending Publication Date: 2022-02-22
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Palladium removal reagents such as 2,4,6-trithiotriazine silica gel, macroporous polystyrene-2,4,6-trithiotriazine acid, sodium thiosulfate, sompex resin-bonded silica gel, cellulose , 3-mercaptopropyl ethyl sulfide silica, 2-mercaptoethyl sulfide ethyl silica, triamine ethyl sulfide amide silica, N-acetyl-L-cysteine ​​ethyl Ester silica, 2-aminoethyl ethyl sulfide silica, Thiofunctional polysiloxane ( MP), methylthiourea sulfide ethyl ethyl silica, ethylenediamine modified silica (BASF SA–FC Si-1), pentaerythritol 2-mercaptoethyl sulfide silica or pentaamine sulfide Ethylamide silica, the above-mentioned resin except palladium material is expensive, not suitable for large-scale production, and the mercapto group is a toxic functional group
Activated carbon adsorption, it is cheap, but after the palladium is removed, the activated carbon particles are easy to adhere to the wall of the reactor, which is not easy to clean, and the effect of activated carbon to remove palladium is very limited

Method used

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  • Preparation method of votioxetine
  • Preparation method of votioxetine
  • Preparation method of votioxetine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029]

[0030] Add 300mL of purified water and 75mL of 1,2-propanediamine (873.25mmol) into a 1000mL three-necked flask successively under stirring, control the temperature at 0-20°C, then slowly add 30.0g of vortioxetine hydrochloride (89.58mmol), Stir for 1 hour. Add 450 mL of ethyl acetate, stir for 2 hours, and let stand for liquid separation. The organic layer was washed successively with 300 mL of saline twice, and 300 mL of purified water twice. Dry over anhydrous sodium sulfate, filter with suction, collect the filtrate, add 1.5 g of activated carbon, stir and decolorize for 1 hour, and then filter with suction. The filtrate was collected and concentrated under reduced pressure until no liquid flowed out. Add 240mL of acetonitrile, heat at 70-80°C and stir to dissolve, add 1.5g of activated carbon, stir for 1 hour to decolorize, and suction filter while it is hot. The filtrate was cooled slowly to 10-15° C., stirred and crystallized for 4 hours, filtered with su...

Embodiment 2

[0032]

[0033] Add 300mL of purified water and 75mL of 1,2-propanediamine (873.25mmol) to a 1000mL three-neck flask successively under stirring, control the temperature at 0-20°C, and add 450mL of ethyl acetate. Add 30.0 g vortioxetine hydrochloride (89.58 mmol) slowly, stir for 3 hours, and let stand to separate the liquids. The organic layer was washed successively with 300 mL of saline twice, and 300 mL of purified water twice. Dry over anhydrous sodium sulfate, filter with suction, collect the filtrate, add 1.5 g of activated carbon, stir and decolorize for 1 hour, and then filter with suction. The filtrate was collected and concentrated under reduced pressure until no liquid flowed out. Add 240mL of acetonitrile, heat at 70-80°C and stir to dissolve, add 1.5g of activated carbon, stir for 1 hour to decolorize, and suction filter while it is hot. The filtrate was cooled slowly to 10-15° C., stirred and crystallized for 4 hours, filtered with suction, and the filter c...

Embodiment 3

[0035]

[0036] Add 200mL of 3moL / L sodium hydroxide solution into a 1000mL three-neck flask under stirring, control the temperature at 0-10°C, slowly add 20.0g of vortioxetine hydrochloride (59.72mmoL), after the addition is complete, continue to control the temperature and stir the reaction 4 After 1 hour, 300 mL of ethyl acetate was added and stirred for 1 hour. Stand still to separate the liquid, collect the organic phase, wash with 300 mL of saline × 2 times, and wash with 300 mL of purified water × 2 times. Dry over anhydrous sodium sulfate and filter. Collect the filtrate, add 1 g of activated carbon and stir for decolorization for 30 minutes, filter with suction, collect the filtrate, and concentrate under reduced pressure until there is no liquid. Add 160mL of acetonitrile, heat at 70-80°C and stir to dissolve, add 1g of activated carbon, stir for 1 hour to decolorize, and suction filter while it is hot. The filtrate was cooled slowly to 10-15° C., stirred and cr...

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PUM

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Abstract

The invention belongs to the field of medicinal chemistry, and relates to a preparation method of votioxetine. According to the method, after a salt of votioxetine is treated with an organic solvent under the condition of a 1,2-propane diamine solution, the compound votioxetine as shown in a formula I is generated, and palladium residues and impurities such as chlorides and acetylated impurities in the prior art can be efficiently reduced with low cost.

Description

technical field [0001] The application belongs to the field of medicinal chemistry and relates to a preparation method of vortioxetine. Background technique [0002] Vortioxetine hydrobromide (Vortioxetine) is a new drug for the treatment of depression. It was jointly developed by Lundbeck Pharmaceuticals of Denmark and Takeda Pharmaceuticals of Japan. It was approved for marketing by the US Food and Drug Administration (FDA) on September 30, 2013. Brintellix, later renamed TRINTELLIX, is used for the treatment of major depression. It was officially launched in the European market in January 2014. [0003] Chinese patent application CN101472906A embodiment 19 discloses the use of palladium catalyst Pddba 2 to catalyze the coupling reaction. [0004] [0005] Obviously, the palladium-catalyzed reaction in step 1 will undoubtedly lead to contamination of the reaction product, because palladium is difficult to separate from the target product. There are strict regulation...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/096
CPCC07D295/096
Inventor 张立志周佳伟邹义芳彭岩吴秀兰
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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